设为首页 加入收藏 期刊导航 网站地图

Pharmacy Information
Vol. 12  No. 03 ( 2023 ), Article ID: 66218 , 9 pages
10.12677/PI.2023.123028

AMP依赖的蛋白激酶在非酒精性脂肪肝中 的作用

刘尚奇1，高峰2，杨艳2，胡艳波1，张慧明1，高倩1，王敏杰1*

1内蒙古医科大学基础医学院，内蒙古 呼和浩特

2内蒙古医科大学药学院，内蒙古 呼和浩特

收稿日期：2023年4月22日；录用日期：2023年5月23日；发布日期：2023年5月30日

摘要

非酒精性脂肪性肝病(NAFLD)，尤其是非酒精性脂肪性肝炎(NASH)已成为肝移植和肝相关性死亡的主要原因。然而，NASH的发病机制仍不清楚。目前，还没有FDA批准的药物来治疗这种疾病。AMP依赖的蛋白激酶(AMPK)可以感知能量状态并调节代谢过程以维持体内平衡。AMPK的活性受到碳水化合物、脂肪和氨基酸等营养物质的调节。AMPK活性因营养缺乏而增加，但在肥胖期间因营养过剩、炎症和某些合成代谢激素(如胰岛素)的过度分泌而受到抑制。抑制肝脏AMPK活性可以使其从单纯性脂肪变性转变为肝细胞死亡，因此激活AMPK可能改善NASH的相关症状。

关键词

非酒精性脂肪性肝病，非酒精性脂肪性肝炎，AMP依赖的蛋白激酶，脂肪变性

AMP-Activated Protein Kinase in Nonalcoholic Fatty Liver Diseases

Shangqi Liu1, Feng Gao2, Yan Yang2, Yanbo Hu1, Huiming Zhang1, Qian Gao1, Minjie Wang1*

1School of Basic Medicine, Inner Mongolia Medical University, Hohhot Inner Mongolia

2School of Pharmacy, Inner Mongolia Medical University, Hohhot Inner Mongolia

Received: Apr. 22nd, 2023; accepted: May 23rd, 2023; published: May 30th, 2023

ABSTRACT

Nonalcoholic fatty liver diseases (NAFLD), especially nonalcoholic steatohepatitis (NASH), have become a major cause of liver transplant and liver-associated death. However, the pathogenesis of NASH is still unclear. Currently, there is no FDA-approved medication to treat this devastating disease. AMP-activated protein kinase (AMPK) senses energy status and regulates metabolic processes to maintain homeostasis. The activity of AMPK is regulated by the availability of nutrients, such as carbohydrates, lipids and amino acids. AMPK activity is increased by nutrient deprivation, and inhibited by overnutrition, inflammation and hypersecretion of certain anabolic hormones, such as insulin, during obesity. The repression of hepatic AMPK activity permits the transition from simple steatosis to hepatocellular death, and thus activation might ameliorate multiple aspects of NASH. Here, we review the pathogenesis of NAFLD and the impact of AMPK activity state on hepatic steatosis, inflammation, liver injury and fibrosis during the transition of NAFL to NASH and liver failure.

Keywords:Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, AMP-Activated Protein Kinase, Steatosis Inflammation

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是代谢功能障碍的主要并发症，属于肥胖的并发症。NAFLD包括非酒精性脂肪肝(non-alcoholic fatty liver, NAFL)和非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)。NAFL的特点是肝脏脂肪变性，卡路里摄入量和运动可以缓解其症状，它通过减少肝内脂肪含量、增加脂肪酸的β氧化、诱导肝保护自噬、过表达过氧化物酶体增殖物激活的受体γ以及减弱肝细胞凋亡和增加胰岛素敏感性来改善NAFL [1] [2] 。NASH的特征性病理改变是脂肪变性、肝脏炎症和不同程度的纤维化 [3] 。后期其可转变为肝硬化、肝功能衰竭和肝细胞癌等严重病变，但目前还没有药物来遏制这种疾病 [4] 。

鉴于目前的研究报道，NASH的发病机制尚不明确。高脂饮食、肥胖和胰岛素抵抗引起的脂肪沉积将导致肝细胞发生损伤，使NAFL逐步向NASH和肝硬化进展 [5] 。就目前研究来看，这种进展过程是由于多种致病因素的并行和协同作用导致的 [6] 。

AMP依赖的蛋白激酶(adenosine 5’-monophosphate (AMP)-activated protein kinase, AMPK)是调节代谢动态平衡的重要能量感受器 [7] 。AMPK的活性将被机体能量过剩所抑制。有研究表明，抑制AMPK可以刺激合成代谢途径，如脂质合成，并减弱分解代谢途径，加重脂肪细胞变性，进而加重肝损伤和肝纤维化程度，广泛的肝细胞凋亡和肝损伤将使NASH向肝硬化和肝细胞癌的转变过程加快 [6] [8] 。此外，激活AMPK将减轻NASH的症状 [8] 。本文综述了AMPK在NASH的生理调节及病理过程中发挥的作用。

2. AMP依赖的蛋白激酶

AMPK是由三个亚基组成的异三聚体丝氨酸/苏氨酸激酶，主要分为三个亚基：起催化作用的α亚基、起支架作用的β亚基和起调节作用的γ亚基 [9] 。其中α亚基有两种亚型：α1和α2，编码基因分别为PRKAA1和PRKAA2；β亚基有β1和β2亚型，编码基因分别为PRKAB1和PRKAB2；γ亚基包括三种亚型：γ1、γ2和γ3，编码基因分别为PRKAG1、PRKAG2和PRKAG3 [10] 。这些亚型之间的功能差异尚不明确，但有研究表明，这些亚型在不同的组织具有不同的分布、调节、亚细胞定位及功能 [11] 。

多种因素可以通过不同亚基的调节AMPK的活性，α亚基末端存在一个保守的苏氨酸(Thr172)位点，它是激活AMPKα激酶活性所必需的磷酸化位点 [12] 。有研究表明，肝脏中存在三种激酶，即肝脏激酶B1 (liver kinase B1, LKB1)、钙调素依赖的蛋白激酶β (calmodul in dependent protein kinase β, CaMKKβ)和转化生长因子β激活的激酶1 (TGFβ Activated Kinase 1, TAK1)可使Thr172位点磷酸化 [13] 。此外，沉默调节蛋白1 (Sirtuin1, SIRT1)是一种依赖于NAD+的脱乙酰酶，它可以使LKB1去乙酰化，从而诱导AMPK磷酸化 [14] 。另一项研究表明，Src家族激酶磷酸化酪氨酸蛋白激酶(fyn-regulating kinase, Fyn)可以使LKB1磷酸化，进而影响AMPK的激活 [15] 。当细胞内钙离子浓度升高时AMPK可以被CaMKKβ直接磷酸化 [16] 。AMPK被TAK1激活的机制尚不清楚，但有研究表明，敲除TAK1可以通过抑制二甲双胍和5-氨基-4甲酰胺咪唑核糖核苷酸(5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside, AICAR)发挥效应进而影响AMPK的激活 [16] [17] 。

腺苷二磷酸(adenosine diphosphate, ADP)结合γ亚基可以变构激活AMPK，同时可以被腺苷三磷酸腺苷(adenosine triphosphate, ATP)抑制 [18] 。AMP可以与γ亚基相互作用使其发生构象变化，进而抑制Thr172磷酸化 [19] 。因此，AMP/ATP比率提高可激活AMPK，通过增加脂质氧化和线粒体生物合成和减少脂肪生成和葡萄糖生成来提高细胞内ATP水平。除ATP外，通过磷酸肌酸变构调节也可以抑制AMPK活性 [20] 。

AMPK活性还会受到脂肪、葡萄糖水平和氨基酸的调控 [21] 。高脂膳食是导致肥胖发生的最主要原因之一，棕榈酸是人类日常脂肪酸摄入的最重要来源。有研究表明，AMPK的活性会被富含棕榈酸酯的高脂肪饮食抑制 [22] ，除此之外还发现棕榈酸急性刺激或慢性刺激对骨骼肌葡萄糖的摄取起到了截然不同的两种作用效果 [23] ，棕榈酸急性刺激通过激活AKt，增加葡萄糖摄取，然而，棕榈酸慢性刺激通过抑制Akt激活减少胰岛素诱导的葡萄糖摄取，除了Akt，AMPK是骨骼肌葡萄糖受体转运通路上另一个关键的调控蛋白 [24] ，AMPK的激活可以诱导葡萄糖转运载体GLUT4从细胞内向细胞膜转运，从而增加葡萄糖的摄取 [25] 。AMPK活性同样可以被过量的氨基酸抑制，其过量堆积将抑制AMPK的活性，并且高蛋白饮食或增加蛋白质摄入量也会抑制AMPK的活化，增加肝脏的雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)磷酸化 [26] 。AMPKβ亚基含有一个保守的糖原结合域，AMPK磷酸化将受到高度分支状态糖原和单一分支的低聚糖抑制 [26] [27] 。此外，人们还发现，AMPK能够响应机体体葡萄糖水平的变化，并在其水平下降的时候被激活，该机制在真核生物中高度保守，从酵母到哺乳动物都已被发现 [28] 。当葡萄糖水平降低时，激活的AMPK能够通过一系列方式维持代谢平衡和机体的正常生理功能。例如，饥饿能够引起血液和组织液中的葡萄糖水平的下降，AMPK在这时被激活，进而促进如肝脏。等组织中脂肪酸的β-氧化，使之转换为利用脂肪酸以代替葡萄糖 [29] 。此外AMPK的活性也可以被一些促炎症细胞因子抑制，如肿瘤坏死因子α (tumor necrosis factor-α, TNF-α)。TNF-α诱导蛋白磷酸酶2C (protein phosphatase, PP2C)的表达可以使Thr172发生去磷酸化，进而抑制AMPK活性 [30] 。综上，AMPK活性受能量状态、营养物质和细胞因子水平等因素调节，在调控代谢过程中发挥着重要作用。

3. AMPK和NAFLD

研究发现，AMPK与代谢性疾病发生率密切相关，包括肥胖、糖尿病和NAFLD。AMPK激活后可以抑制脂质合成和通过LKB1依赖的方式刺激脂肪酸氧化来降低肝脏甘油三酯的含量 [8] 。此外，小分子AMPK激动剂与小分子AMPK激动剂联合作用于小鼠和人的原代肝细胞，可增强抗糖尿病药物二甲双胍抑制脂肪生成和促进脂肪酸氧化的作用 [31] 。虽然AMPK在NAFL和NASH中发挥作用的机制尚不清除，但激活AMPK可以明显改善两者的症状。

3.1. 肝损伤

肝脏是一个高度血管化的大型器官，具有代谢稳态、解毒和免疫的核心功能，是参与内源性、外源性物质解毒和代谢的器官。由于其作用，肝脏经常受到各种压力、损伤，这些损伤可能导致细胞死亡和肝功能障碍。目前，国际上有大量研究表明，肝细胞癌发生发展最主要的因素就是肝细胞在致病因素作用下出现大量异常死亡 [32] 。NASH肝损伤的一个重要原因是多种类型的细胞出现大量死亡。正常情况下的细胞凋亡都是在新陈代谢动态平衡下进行的，但过高水平的细胞凋亡刺激会破坏该平衡，导致细胞出现大量的死亡以至于引起肝脏严重损伤。如今，单纯肝脂肪变性被认为是一种良性的临床病程，但非酒精性脂肪性肝炎(NASH)是更具侵袭性的疾病形式，导致NAFLD患者发生肝硬化、肝细胞癌和肝脏相关死亡率的风险增加 [15] 。近期有研究表明，NASH的肝损伤除了大面积肝细胞的凋亡也存在其他类型的细胞，证明肝脏损伤机制中有多种类型的细胞与其相关 [33] 。

肝损伤的作用机制较为复杂，其作用机制与多种途径相关。肝脏作为胆汁酸的主要合成和转运场所，胆汁酸的代谢失调，会引起肝内胆汁淤积症状的发生，严重者可从肝损伤转化为纤维化、肝硬化、肝肿瘤甚至肝衰竭 [34] 。NASH的发生机制包括脂毒性、内质网应激、氧化应激、线粒体功能障碍等激活了具有介导肝细胞死亡能力的信号途径 [35] 。最近有研究通过建立由胆碱缺乏高脂饮食(CD-HFD，60%脂肪，0.1%蛋氨酸，氨基酸，不添加胆碱)诱导的NASH模型，发现肝脏特异性AMPKα1/α2基因敲除会加重肝损伤，证明在防止肝细胞死亡和肝损伤中，激活AMPK是非常有必要的。NASH的发展过程中，在肝细胞中由Caspase介导的凋亡信号通路被激活，从而导致肝细胞死亡并形成恶性循环。NAFLD和肥胖症期间AMPK被明显抑制，释放caspase-6以启动肝细胞的凋亡，表明激动剂A769662激活AMPK后，即使是在NASH发病后也能在治疗肝损伤中起着重大作用 [6] 。

3.2. 肝脏脂肪变性

肝脏脂肪变性是由于新生脂肪生成和酯化作用的增加所导致的，异位脂肪中会出现大小不等，多少不一的游离脂肪滴，在脂肪变性中最为常见。肝脏的脂质代谢对维持机体稳态有着至关重要的作用，肝细胞可合成和分泌胆汁酸，参与脂质消化，同时它也是合成、转化及排出胆固醇的关键器官，它对甘油三酯和极低密度脂蛋白代谢也具有重要作用 [36] 。乙酰辅酶A羧化酶(acetyl CoA carboxylase, ACC)是目前最有潜力的脂肪肝炎治疗靶点，其抑制剂可明显改善肝脏脂肪变性、炎症和纤维化，AMPK作为其抑制剂可以减少肝脏总脂肪的储存 [10] ，血清游离脂肪酸水平的升高则会增加肝脏脂肪堆积 [13] 。综上，AMPK可降低脂质分解，减少肝脏中游离脂肪酸水平，减轻肝脏脂肪变性。

目前也有研究表明激活AMPK可以使胆固醇和甘油三酯的合成降低，从而减少肝脏脂肪变性量。胆固醇和甘油三酯的组成受胆固醇调节元件结合蛋白(sterol-regulatory element binding proteins, SREBPs)调节，其中SREBP-1激活后会使FASN和ACC的表达上调，促进新生脂肪生成，而胆固醇合成基因的表达会被SREBP-2的激活上调，SREBP-1和SREBP-2会被AMPK的直接活化抑制，导致肝脏胆固醇合成和新生脂肪生成减少，进而减少肝脏脂肪的变性。

Smith等人的综述中确定了大量对脂肪肝治疗具有有益效果的AMPK激动剂，同时也强调了其显著相关性 [37] 。目前使用最广泛的的AMPK激动剂是二甲双胍，它可以显著降低啮齿类动物的肝脏脂肪变性 [38] 。AMPK激动剂A-769662激活后，由高脂饮食诱导的NAFL中的肝脏脂肪含量会随之降低 [39] 。Nadia等人的研究表明，肝脏特异性AMPK敲除小鼠表现出正常的肝脏脂质稳态，与肝脏脂肪变性相关的AMPK活性降低可能是肝脏代谢变化的结果 [8] 。在脂肪组织中，线粒体呼吸的增加会导致循环系统内脂肪酸含量减少，进而减少肝脏脂肪变性。AMPK除了可诱导线粒体产生增加，还可以通过磷酸化和激活UNC-51样自噬激活激酶1来诱导有丝分裂吞噬 [40] 。

除此之外，目前又发现很多改善肝脏脂肪变性的药物，例如有研究表明表没食子儿茶素没食子酸酯(epigallocatechin gallate, EGCG)可预防非酒精性脂肪肝，并可显著减轻肝损伤及肝脂肪变性 [40] [41] 。治疗糖尿病的药物普氏菌，可改善脂肪组织和肝脏的炎症，而且可以通过抑制肝脏脂肪生成酶的活性来改善肝脏脂肪变性 [41] 。

综上所述，AMPK被诱导激活后会对肝脏代谢产生有益作用，降低脂肪变性。

3.3. 肝脏炎症

肝脏内的炎症反应是NAFL向NASH发展的标志。在NASH发生发展过程中，来自骨髓的巨噬细胞在肝脏内驻扎，与Kupffer细胞合作导致肝炎发生进程加快 [42] 。Kupffer细胞是卵黄来源的驻留在肝脏的一类巨噬细胞，可以局部增殖和自我维持。巨噬细胞在肝脏免疫平衡和NASH中发挥重要作用。有研究表明，肝活检标本中肝冠状结构的计数与NASH患者肝细胞死亡、肝细胞气球样变性和纤维化的组织学标志有关。在疾病模型中，肝巨噬细胞在小鼠饮食模型中的作用也被证实，如高脂饮食和蛋氨酸胆碱缺乏饮食。在受到刺激后，Kupffer细胞招募额外的免疫细胞，包括中性粒细胞和Ly6C高表达的炎性单核细胞(lymphocyte antigen 6C high expression, Ly6cHI)，再分化为CD11b + F4/80+经典激活的巨噬细胞(M1型)，从而分泌促炎细胞因子和活性氧因子 [43] 。

另外，在诱发肝脏炎症的因素中还有内质网应激、线粒体功能障碍、氧化应激、脂肪毒性等。活性氧在NADPH氧化酶的作用下生成，在氧化应激刺激信号诱导下在肝脏中表达上调。巨噬细胞是NADPH氧化酶产生活性氧(reactive oxygen species, ROS)机制中的主要来源。研究证明，在体内巨噬细胞中危险相关分子机制会诱导ROS的形成 [44] 。当脂肪酸超负荷时，肝细胞中的脂肪酸β氧化增加，促进ROS的产生。脂肪酸可以转化为甘油三酯，而甘油三酯又通过极低密度脂蛋白运输出来或者储存在脂滴中，脂滴是通常被认为无毒的中性形式的脂类。过量的脂肪酸还会导致二酰甘油和神经酰胺数量增加，可能会通过促进ROS的过度产生和触发肝细胞凋亡来诱导脂毒性 [45] 。另外，氧化应激作用上调肝脏脂质过氧化，此过程不需要酶的加入，而这个过程中产生的物质又在促进ROS的生成，导致这一连贯过程形成一个恶性循环。蛋白质错误折叠或者没有折叠的话会导致内质网应激，而内质网应激会加速ROS的生成，继而诱发炎症 [46] 。

体内巨噬细胞蓄积时其中的趋化因子配体2 (chemokine ligand 2, CCL2)是重要分子。c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)和k基因结合核因(nuclear factor-k-gene binding, NF-kB)介导的各种促炎信号通路会调节CCL2的表达。TNFα和棕榈酸酯诱导的NF-kB信号通路激活并下调离不开通过表达固有活性激活的AMPK或由激动剂AICAR激活的AMPK的调节。在其机理上，NF-kB会受AMPK抑制，而该通路被抑制又会导致NF-kB靶基因表达下调。大多数研究证明，AMPK先导致unc-51样激酶1 (unc-51-like kinase 1, ULK1)磷酸化，再诱导TANK结合激酶1 (Serine/threonine-protein kinase TBK1)磷酸化，TBK1又磷酸化NF-kB诱导激酶，诱导其降解 [47] 。因此，在NAFLD中非典型NF-kB途径的异常激活是因为AMPK激活而导致NF-kB诱导激酶(NF-kB-inducing kinase, NIK)降解，NIK再诱导非典型NF-kB途径的减弱 [48] 。此外，被激动剂A-769662激活的AMPK会抑制IL-1β诱导的JNK激活 [49] 。因此，要减少CCL2的表达可以通过AMPK抑制促炎信号通路来实现。另外也有研究表明，下游转录因子中的过氧化物酶体增殖物激活受体-γ共激活因子-1α (Peroxisome proliferator-activated receptor-γ co-activator-1α, PGC1α)和FoxO家族蛋白可以通过调节基因表达参与AMPK的抗炎作用 [50] 。

AMPK减弱体内炎症反应并不仅仅是通过抑制促炎信号，还可以通过抗氧化功能来减轻炎症。激活的AMPK会使胞质内ROS产生减少和NAD(P)H氧化酶基因表达减少 [51] 。线粒体ROS产生的减少是由于被激活的AMPK通过上调PGC1α靶基因的表达量来调节。ROS减少会上调NLRP3的激活，以减少炎症的发生 [51] 。因此，ROS在肝脏炎症的发生发展中起着功不可没的作用。AMPK减轻氧化应激的作用是由于它的激活增加了过氧化氢酶和超氧化物歧化酶2的表达。研究证明，AMPK可以被类似辅酶Q10的抗氧化剂所激活继而抑制NLRP3的激活 [52] 。硫氧还蛋白的表达受AMPK-FoxO 3途径的调节。因此可以证明，AMPK通过抑制NLRP3炎症小体的激活，来预防肝脏炎症的发生发展。

3.4. 肝纤维化

目前在临床治疗上，确定NASH严重程度时肝纤维化占重要地位。肝脏纤维化恶性发展往往会导致NASH进展为肝硬变。在正常因素作用下的纤维化是一种伤口愈合过程，在患者治疗过程中功不可没，它会形成多余的纤维结缔组织以取代正常的实质组织 [53] 。正常的纤维化在损伤过程中是组织修复必不可少的环节，但一旦超出正常范围就会引起组织严重损伤。多种致病因素如氧化应激、肝损伤和肝脏炎症会诱导肝脏纤维化，该过程一般会在NASH早期阶段中发现，如肝损伤程度严重的话，由肝脏纤维化生成的瘢痕组织也会反过来加重肝脏纤维化程度使其变成恶性的进行性肝损伤最后导致肝硬变的发生。肝损伤加重会引起肝脏纤维化的发生，而纤维化反过来又使肝脏损伤愈发严重。因此，NASH治疗的最终治疗目标应放在减轻肝纤维化并恢复肝功能上。

肝星状细胞(hepatic stellate cells, HSCs)在慢性肝脏疾病中是肝脏纤维化的直接介质。在由内皮细胞产生的血小板衍生生长因子、巨噬细胞产生的转化生长因子β以及其他相关细胞产生的炎性细胞因子和生长因子作用下肝星状细胞会出现增殖过多和转分化。这些炎性因子和细胞因子激活HSCs后，HSCs转分化为肌成纤维细胞，而肌成纤维细胞又会产生大量的细胞外基质蛋白 [54] 。因此，肝脏的动态平衡被纤维和细胞外基质(extracellular matrix, ECM)的大量聚集打破从而加快了肝脏纤维化转变为肝硬变甚至肝细胞癌的过程 [31] 。

研究发现，AMPK在不同的NASH模型中被激活后对肝脏纤维化和肝脏损伤有积极的治疗作用 [6] 。高脂胆碱缺乏饮食诱导的NASH的肝损伤会被A-769662激活的AMPK所改善，且它还可以进一步减轻肝脏纤维化。在治疗晚期肝癌中，索拉非尼是一种被寄予厚望的一线药物，AMPK可以被小剂量的索拉非尼激活并诱导减轻实验猴和小鼠模型中NASH肝脏纤维化。另外，趋化因子配体4(chemokine ligand 4, CCL4)也被证明在肝脏纤维化和肝脏损伤模型中起着重要作用，注射CCL4可以通过非脂质依赖的方式诱导调节肝损伤和肝纤维化 [55] 。也是在同一个小鼠模型中，AMPK被激活后抑制HSC的增殖和下调纤维化基因包括TGFB、ACTA2、NOX4的表达，对治疗肝脏纤维化起着正向作用。激活AMPK可以抑制HSCs的激活和ROS的产生，从而使肝脏损伤和纤维化降低 [56] 。此外，多种研究表明，在纤维化过程中HSCs会被一种细胞因子诱导激活，据研究，该纤维化细胞因子TGFβ主要来自肝脏巨噬细胞 [56] 。TGFβ诱导的HSC中纤维化基因的表达会被激活的AMPK下调。由此可见，AMPK可以被多种因素激活改善肝纤维化。

4. 结论与展望

AMPK是调节代谢动态平衡的重要能量感受器。越来越多的证据表明，AMPK活性在包括肥胖、糖尿病和NAFLD在内的代谢紊乱中受到抑制。AMPK的抑制与NAFLD的炎症、肝损伤和纤维化有关。AMPK激活通过不同的机制改善NASH肝脏脂肪变性、炎症、肝损伤和纤维化的症状。在AMPK活性增加导致心肌细胞肥大的情况下，肝细胞靶向给药激活AMPK对NASH的治疗可能具有重要意义。

基金项目

国家自然科学基金项目(81703511)；内蒙古自治区自然科学基金项目(2019MS08136)；内蒙古医科大学“致远人才”项目(ZY0130012)；内蒙古医科大学面上项目(YKD2021MS019)。

文章引用

刘尚奇,高 峰,杨 艳,胡艳波,张慧明,高 倩,王敏杰. AMP依赖的蛋白激酶在非酒精性脂肪肝中的作用
AMP-Activated Protein Kinase in Nonalcoholic Fatty Liver Diseases[J]. 药物资讯, 2023, 12(03): 224-232. https://doi.org/10.12677/PI.2023.123028

参考文献

  1. 1. Jung, T.W., Park, H.S., Choi, G.H., Kim, D. and Lee, T. (2018) β-Aminoisobutyric Acid Attenuates LPS-Induced Inflammation and Insulin Resistance in Adipocytes through AMPK-Mediated Pathway. Journal of Biomedical Science, 25, Article No. 27. https://doi.org/10.1186/s12929-018-0431-7

  2. 2. Farzanegi, P., Dana, A., Ebrahimpoor, Z., Asadi, M. and Azarbayjani, M.A. (2019) Mechanisms of Beneficial Effects of Exercise Training on Non-Alcoholic Fatty Liver Disease (NAFLD): Roles of Oxidative Stress and Inflammation. European Journal of Sport Science, 19, 994-1003. https://doi.org/10.1080/17461391.2019.1571114

  3. 3. Friedman, S.L., Neuschwander-Tetri, B.A., Rinella, M. and Sanyal, A.J. (2018) Mechanisms of NAFLD Development and Thera-peutic Strategies. Nature Medicine, 24, 908-922. https://doi.org/10.1038/s41591-018-0104-9

  4. 4. Lindenmeyer, C.C. and McCullough, A.J. (2018) The Natural History of Nonalcoholic Fatty Liver Disease-An Evolving View. Clinics in Liver Disease, 22, 11-21. https://doi.org/10.1016/j.cld.2017.08.003

  5. 5. Rinella, M.E. and Sanyal, A.J. (2016) Management of NAFLD: A Stage-Based Approach. Nature Reviews Gastroenterology & Hepatology, 13, 196-205. https://doi.org/10.1038/nrgastro.2016.3

  6. 6. Zhao, P., Sun, X.L., Chaggan, C., Liao, Z.J., Wong, K.I., He, F., Saltiel, A.R., et al. (2020) An AMPK-Caspase-6 Axis Controls Liver Damage in Nonalcoholic Steatohepatitis. Sci-ence, 367, 652-660. https://doi.org/10.1126/science.aay0542

  7. 7. Cheung, P.C., Salt, I.P., Davies, S.P., Hardie, D.G. and Carling, D. (2000) Characterization of AMP-Activated Protein Kinase γ-Subunit Isoforms and Their Role in AMP Binding. Biochemical Journal, 346, 659-669. https://doi.org/10.1042/bj3460659

  8. 8. Boudaba, N., Marion, A., Huet, C., Pierre, R., Viollet, B. and Foretz, M. (2018) AMPK Re-Activation Suppresses Hepatic Steatosis But Its Downregulation Does Not Promote Fatty Liver Development. eBioMedicine, 28, 194-209. https://doi.org/10.1016/j.ebiom.2018.01.008

  9. 9. Hawley, S.A., Davison, M., Woods, A., Davies, S.P., Beri, R.K., Carling, D. and Hardie, D.G. (1996) Characterization of the AMP-Activated Protein Kinase Kinase from Rat Liver and Identification of Threonine 172 as the Major Site at Which It Phosphorylates AMP-Activated Protein Kinase. Journal of Biological Chemistry, 271, 27879-27887. https://doi.org/10.1074/jbc.271.44.27879

  10. 10. Salt, I., Celler, J.W., Hawley, S.A., Prescott, A., Woods, A., Carling, D. and Hardie, D.G. (1998) AMP-Activated Protein Kinase: Greater AMP Dependence, and Preferential Nuclear Localization, of Complexes Containing the α2 Isoform. Biochemical Journal, 334, 177-187. https://doi.org/10.1042/bj3340177

  11. 11. Pinter, K., Grignani, R.T., Watkins, H. and Redwood, C. (2013) Lo-calisation of AMPK γ Subunits in Cardiac and Skeletal Muscles. Journal of Muscle Research and Cell Motility, 34, 369-378. https://doi.org/10.1007/s10974-013-9359-4

  12. 12. Mitchelhill, K.I., Michell, B.J., House, C.M., Sta-pleton, D., Dyck, J., Gamble, J. and Kemp, B.E. (1997) Posttranslational Modifications of the 5’-AMP-Activated Protein Kinase β1 Subunit. Journal of Biological Chemistry, 272, 24475-24479. https://doi.org/10.1074/jbc.272.39.24475

  13. 13. Hawley, S.A., Pan, D.A., Mustard, K.J., Ross, L., Bain, J., Edelman, A.M. and Hardie, D.G. (2005) Calmodulin-Dependent Protein Kinase Kinase-β Is an Alternative Upstream Kinase for AMP-Activated Protein Kinase. Cell Metabolism, 2, 9-19. https://doi.org/10.1016/j.cmet.2005.05.009

  14. 14. Howitz, K.T., Bitterman, K.J., Cohen, H.Y., Lamming, D.W., Lavu, S., Wood, J.G. and Sinclair, D.A. (2003) Small Molecule Activators of Sirtuins Extend Saccharomyces cerevisiae Lifespan. Nature, 425, 191-196. https://doi.org/10.1038/nature01960

  15. 15. Yamada, E., Pessin, J.E., Kurland, I.J., Schwartz, G.J. and Bastie, C.C. (2010) Fyn-Dependent Regulation of Energy Expenditure and Body Weight Is Mediated by Tyrosine Phos-phorylation of LKB1. Cell Metabolism, 11, 113-124. https://doi.org/10.1016/j.cmet.2009.12.010

  16. 16. Hurley, R.L., Anderson, K.A., Franzone, J.M., Kemp, B.E., Means, A.R. and Witters, L.A. (2005) Ca2+/Calmodulin-Dependent Protein Kinase Kinase-β Acts Upstream of AMP-Activated Protein Kinase in Mammalian Cells. Cell Metabolism, 2, 21-33. https://doi.org/10.1016/j.cmet.2005.06.005

  17. 17. Inokuchi-Shimizu, S., Park, E.J., Roh, Y.S., Yang, L., Zhang, B., Song, J. and Seki, E. (2014) TAK1-Mediated Autophagy and Fatty Acid Oxidation Prevent Hepatosteatosis and Tumorigenesis. Journal of Clinical Investigation, 124, 3566-3578. https://doi.org/10.1172/JCI74068

  18. 18. Mihaylova, M.M. and Shaw, R.J. (2011) The AMPK Signalling Pathway Coordinates Cell Growth, Autophagy and Metabolism. Nature Cell Biology, 13, 1016-1023. https://doi.org/10.1038/ncb2329

  19. 19. Suter, M., Riek, U., Tuerk, R., Schlattner, U., Wallimann, T. and Neu-mann, D. (2006) Dissecting the Role of 5’-AMP for Allosteric Stimulation, Activation, and Deactivation of AMP-Activated Protein Kinase. Journal of Biological Chemistry, 281, 32207-32216. https://doi.org/10.1074/jbc.M606357200

  20. 20. Hawley, S.A., Davison, M., Woods, A., Davies, S.P., Beri, R.K., Carling, D. and Hardie, D.G. (1996) Dual Regulation of the AMP-Activated Protein Kinase Provides a Novel Mechanism for the Control of Creatine Kinase in Skeletal Muscle. The EMBO Journal, 17, 1688-1699. https://doi.org/10.1093/emboj/17.6.1688

  21. 21. Zhao, P., Wong, K.I., Sun, X., Reilly, S.M., Uhm, M., Liao, Z. and Saltiel, A.R. (2018) TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell, 172, 731-743. https://doi.org/10.1016/j.cell.2018.01.007

  22. 22. Wu, Y., Song, P., Xu, J., Zhang, M. and Zou, M.H. (2007) Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-Activated Protein Kinase. Journal of Biological Chemistry, 282, 9777-9788. https://doi.org/10.1074/jbc.M608310200

  23. 23. Pu, J., Peng, G., Li, L., Na, H., Liu, Y. and Liu, P. (2011) Palmitic Acid Acutely Stimulates Glucose Uptake via Activation of Akt and ERK1/2 in Skeletal Muscle Cells. Journal of Lipid Research, 52, 1319-1327. https://doi.org/10.1194/jlr.M011254

  24. 24. Salvado, L., Coll, T., Gomez-Foix, A.M., Salmeron, E., Barroso, E., Palomer, X. and Vazquez-Carrera, M. (2013) Oleate Prevents Saturated-Fatty-Acid-Induced ER Stress, Inflammation and Insulin Resistance in Skeletal Muscle Cells through an AMPK-Dependent Mechanism. Diabetologia, 56, 1372-1382. https://doi.org/10.1007/s00125-013-2867-3

  25. 25. Steinbusch, L.K., Schwenk, R.W., Ouwens, D.M., Diamant, M., Glatz, J.F. and Luiken, J.J. (2011) Subcellular Trafficking of the Substrate Transporters GLUT4 and CD36 in Cardiomyocytes. Cellular and Molecular Life Sciences, 68, 2525-2538. https://doi.org/10.1007/s00018-011-0690-x

  26. 26. McBride, A., Ghilagaber, S., Nikolaev, A. and Hardie, D.G. (2009) The Glycogen-Binding Domain on the AMPK β Subunit Allows the Kinase to Act as a Glycogen Sensor. Cell Metabolism, 9, 23-34. https://doi.org/10.1016/j.cmet.2008.11.008

  27. 27. Hurley, R.L., Barre, L.K., Wood, S.D., Anderson, K.A., Kemp, B.E., Means, A.R. and Witters, L.A. (2006) Regulation of AMP-Activated Protein Kinase by Multisite Phosphory-lation in Response to Agents That Elevate Cellular cAMP. Journal of Biological Chemistry, 281, 36662-36672. https://doi.org/10.1074/jbc.M606676200

  28. 28. Hardie, D.G. and Carling, D. (1997) The AMP-Activated Protein Kinase—Fuel Gauge of the Mammalian Cell? European Journal of Biochemistry, 246, 259-273. https://doi.org/10.1111/j.1432-1033.1997.00259.x

  29. 29. Savage, D.B., Choi, C.S., Samuel, V.T., Liu, Z.X., Zhang, D., Wang, A. and Shulman, G.I. (2006) Reversal of Diet-Induced Hepatic Steatosis and Hepatic Insulin Resistance by Antisense Oligonucleotide Inhibitors of Acetyl-CoA Carboxylases 1 and 2. Journal of Clinical In-vestigation, 116, 817-824. https://doi.org/10.1172/JCI27300

  30. 30. Steinberg, G.R., Michell, B.J., van Denderen, B.J., Watt, M.J., Carey, A.L., Fam, B.C. and Kemp, B.E. (2006) Tumor Necrosis Factor α-Induced Skeletal Muscle Insulin Resistance Involves Suppression of AMP-Kinase Signaling. Cell Metabolism, 4, 465-474. https://doi.org/10.1016/j.cmet.2006.11.005

  31. 31. Kraegen, E.W., Saha, A.K., Preston, E., Wilks, D., Hoy, A.J., Cooney, G.J. and Ruderman, N.B. (2006) Increased Malonyl-CoA and Diacylglycerol Content and Reduced AMPK Activity Accompany Insulin Resistance Induced by Glucose Infusion in Muscle and Liver of Rats. American Journal of Physiology-Endocrinology and Metabolism, 290, E471-E479. https://doi.org/10.1152/ajpendo.00316.2005

  32. 32. Lessard, S.J., Chen, Z.P., Watt, M.J., Hashem, M., Reid, J.J., Febbraio, M.A. and Hawley, J.A. (2006) Chronic Rosiglitazone Treatment Restores AMPKα2 Activity in Insu-lin-Resistant Rat Skeletal Muscle. American Journal of Physiology-Endocrinology and Metabolism, 290, E251-E257. https://doi.org/10.1152/ajpendo.00096.2005

  33. 33. Brunt, E.M., Wong, V.W., Nobili, V., Day, C.P., Sookoian, S., Maher, J.J. and Rinella, M.E. (2015) Nonalcoholic Fatty Liver Disease. Nature Reviews Disease Primers, 1, Ar-ticle No. 15080. https://doi.org/10.1038/nrdp.2015.80

  34. 34. 朱世超, 郑学敏, 周植星, 等. 胆汁酸及受体与肝癌的研究进展[J]. 中国新药杂志, 2017, 26(5): 525-529.

  35. 35. Ropelle, E.R., Pauli, J.R., Fernandes, M.F., Rocco, S.A., Marin, R.M., Morari, J. and Carvalheira, J.B. (2008) A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammaliantarget of Rapamycin (mTOR) in High-Protein Diet—Induced Weight Loss. Diabetes, 57, 594-605. https://doi.org/10.2337/db07-0573

  36. 36. Nguyen, K., Hebert, K., McConnell, E., Cullen, N., Cheng, T., Awoyode, S. and Burow, M.E. (2023) LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma. Pharmacological Research, 192, Article ID: 106757. https://doi.org/10.1016/j.phrs.2023.106757

  37. 37. Smith, B.K., Marcinko, K., Desjardins, E.M., Lally, J.S., Ford, R.J. and Steinberg, G.R. (2016) Treatment of Nonalcoholic Fatty Liver Disease: Role of AMPK. American Journal of Physiology-Endocrinology and Metabolism, 311, E730-E740. https://doi.org/10.1152/ajpendo.00225.2016

  38. 38. Lin, H.Z., Yang, S.Q., Chuckaree, C., Kuhajda, F., Ronnet, G. and Diehl, A.M. (2000) Metformin Reverses Fatty Liver Disease in Obese, Leptin-Deficient Mice. Nature Medicine, 6, 998-1003. https://doi.org/10.1038/79697

  39. 39. Cokorinos, E.C., Delmore, J., Reyes, A.R., Albuquerque, B., Kjobsted, R., Jorgensen, N.O. and Miller, R.A. (2017) Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-Human Primates and Mice. Cell Metabolism, 25, 1147-1159. https://doi.org/10.1016/j.cmet.2017.04.010

  40. 40. Hurley, R.L., Anderson, K.A., Franzone, J.M., Kemp, B.E., Means, A.R. and Witters, L.A. (2005) The Ca2+/Calmodulin-Dependent Protein Kinase Kinases Are AMP-Activated Protein Kinase Kinases. Journal of Biological Chemistry, 280, 29060-29066. https://doi.org/10.1074/jbc.M503824200

  41. 41. Ding, S.B., Chu, X.L., Jin, Y.X., Jiang, J.J., Zhao, X. and Yu, M. (2023) Epigallocatechin Gallate Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity by Targeting Mitochondrial ROS-Mediated Ferroptosis. Frontiers in Pharmacology, 14, Article ID: 1148814. https://doi.org/10.3389/fphar.2023.1148814

  42. 42. Lanthier, N., Molendi-Coste, O., Horsmans, Y., van Rooijen, N., Cani, P.D. and Leclercq, I.A. (2010) Kupffer Cell Activation Is a Causal Factor for Hepatic Insulin Resistance. American Journal of Physiology-Gastrointestinal and Liver Physiology, 298, G107-G116. https://doi.org/10.1152/ajpgi.00391.2009

  43. 43. Kazankov, K., Jorgensen, S., Thomsen, K.L., Moller, H.J., Vilstrup, H., George, J. and Gronbaek, H. (2019) The Role of Macrophages in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Nature Reviews Gastroenterology & Hepatology, 16, 145-159. https://doi.org/10.1038/s41575-018-0082-x

  44. 44. Woods, A., Dickerson, K., Heath, R., Hong, S.P., Momcilovic, M., Johnstone, S.R. and Carling, D. (2005) Ca2+/Calmodulin-Dependent Protein Kinase Kinase-β Acts Upstream of AMP-Activated Protein Kinase in Mammalian Cells. Cell Metabolism, 2, 21-33. https://doi.org/10.1016/j.cmet.2005.06.005

  45. 45. Mendez-Sanchez, N., Cruz-Ramon, V.C., Ramirez-Perez, O.L., Hwang, J.P., Barranco-Fragoso, B. and Cordova-Gallardo, J. (2018) New Aspects of Lipotoxicity in Nonal-coholic Steatohepatitis. International Journal of Molecular Sciences, 19, Article 2034. https://doi.org/10.3390/ijms19072034

  46. 46. Lan, F., Cacicedo, J.M., Ruderman, N. and Ido, Y. (2008) SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1. Possible Role in AMP-Activated Protein Kinase Activation. Journal of Biological Chemistry, 283, 27628-27635. https://doi.org/10.1074/jbc.M805711200

  47. 47. Hardie, D.G., Ross, F.A. and Hawley, S.A. (2012) AMPK: A Nutrient and Energy Sensor That Maintains Energy Homeostasis. Nature Reviews Molecular Cell Biology, 13, 251-262. https://doi.org/10.1038/nrm3311

  48. 48. Sanders, M.J., Grondin, P.O., Hegarty, B.D., Snowden, M.A. and Carling, D. (2007) Investigating the Mechanism for AMP Activation of the AMP-Activated Protein Kinase Cascade. Biochemical Journal, 403, 139-148. https://doi.org/10.1042/BJ20061520

  49. 49. Riek, U., Scholz, R., Konarev, P., Rufer, A., Suter, M., Nazabal, A. and Wallimann, T. (2008) Structural Properties of AMP-Activated Protein Kinase: Dimerization, Molecular Shape, and Changes upon Ligand Binding. Journal of Biological Chemistry, 283, 18331-18343. https://doi.org/10.1074/jbc.M708379200

  50. 50. Daval, M., Foufelle, F. and Ferre, P. (2006) Functions of AMP-Activated Protein Kinase in Adipose Tissue. The Journal of Physiology, 574, 55-62. https://doi.org/10.1113/jphysiol.2006.111484

  51. 51. Muse, E.D., Obici, S., Bhanot, S., Monia, B.P., McKay, R.A., Rajala, M.W. and Rossetti, L. (2004) Role of Resistin in Diet-Induced Hepatic Insulin Resistance. Journal of Clinical Investigation, 114, 232-239. https://doi.org/10.1172/JCI200421270

  52. 52. Wang M.Y. and Unger, R.H. (2005) Role of PP2C in Cardiac Lipid Accumulation in Obese Rodents and Its Prevention by Troglitazone. American Journal of Physiology-Endocrinology and Metabolism, 288, E216-E221. https://doi.org/10.1152/ajpendo.00004.2004

  53. 53. Liang, Z., Li, T., Jiang, S., Xu, J., Di, W., Yang, Z., Hu, W. and Yang, Y. (2017) AMPK: A Novel Target for Treating Hepatic Fibrosis. Oncotarget, 8, 62780-62792. https://doi.org/10.18632/oncotarget.19376

  54. 54. Lee, U.E. and Friedman, S.L. (2011) Mechanisms of Hepatic Fibrogenesis. Best Practice & Research Clinical Gastroenterology, 25, 195-206. https://doi.org/10.1016/j.bpg.2011.02.005

  55. 55. Li, J., Pan, Y., Kan, M., Xiao, X., Wang, Y., Guan, F. and Chen, L. (2014) Hepatoprotective Effects of Berberine on Liver Fibrosis via Activation of AMP-Activated Protein Kinase. Life Sciences, 98, 24-30. https://doi.org/10.1016/j.lfs.2013.12.211

  56. 56. Kang, J.W., Hong, J.M. and Lee, S.M. (2016) Melatonin En-hances Mitophagy and Mitochondrial Biogenesis in Rats with Carbon Tetrachloride-Induced Liver Fibrosis. Journal of Pineal Research, 60, 383-393. https://doi.org/10.1111/jpi.12319

    57. NOTES

    *通讯作者。

期刊菜单